Design synthesis and evaluation of arylamino propoxyphenyl indoles for potential atypical antipsychotic activity

Introduction A series of substituted indole derivatives have been synthesized and evaluated for their atypical antipsychotic activity Compared to traditional neuroleptics, second-generation or “atypical” antipsychotics offer a more favorable therapeutic profile against both positive and negative symptoms of schizophrenia.Methods The compounds were designed based on their physicochemical similarity studies to standard drugs and in silico (docking studies) with 5-HT2A and D2 receptors. The prepared compounds were evaluated for atypical antipsychotic activity in animal models of dopaminergic (apomorphine-induced mesh climbing behavior and stereotypy) and serotonergic antagonism (1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) induced head twitch assay). All the test compounds showed. The potential of these compounds to penetrate the blood-brain barrier (log BB) was computed through an online software program, and the values obtained for the compounds suggest good potential for brain permeation.Results In-silico (docking studies) suggested good binding of the test compounds to the 5-HT2A and D2 receptors and a hypothetical binding model for the target compounds was postulated. The prepared test compounds, designated as 8 to 15, exhibited an atypical antipsychotic profile in the pharmacological assays with a mechanistic profile of combined 5-HT2A and D2 antagonism.Conclusion The study has afforded novel indole-based lead molecules with potential atypical antipsychotic effect.